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Guidelines for Developmental Toxicity Risk Assessment

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Guidelines for Developmental Toxicity Risk Assessment EPA/600/FR-91/001 December 1991 Guidelines for Developmental Toxicity Risk Assessment Published on December 5, 1991, Federal Register 56(234):63798-63826 Risk Assessment Forum U.S. Environmental Protection Agency Washington, DC DISCLAIMER This document has been reviewed in accordance with U.S. Environmental Protection Agency policy and approved for publication. Mention of trade names or commercial products does not constitute endorsement or recommendation for use. Note: This document represents the final guidelines. A number of editorial corrections have been made during conversion and subsequent proofreading to ensure the accuracy of this publication. ii CONTENTS Lists of Tables and Figures ........................................................v Federal Register Preamble ....................................................... vi Part A: Guidelines for Developmental Toxicity Risk Assessment 1. Introduction ................................................................1 2. Definitions and Terminology ....................................................3 3. Hazard Identification/Dose-Response Evaluation of Agents That Cause Developmental Toxicit y 4 3.1. Developmental Toxicity Studies: Endpoints and Their Interpretation ..................5 3.1.1. Laboratory Animal Studies ..........................................5 3.1.1.1 Endpoints of Maternal Toxicity . 7 3.1.1.2. Endpoints of Developmental Toxicity: Altered Survival, Growth, and Morphological Development ........................9 3.1.1.3. Endpoints of Developmental Toxicity: Functional Deficits ...........13 3.1.1.4. Overall Evaluation of Maternal and Developmental Toxicity ..........17 3.1.1.5. Short-Term Testing in Developmental Toxicity ...................18 3.1.1.6. Statistical Considerations ...................................20 3.1.2. Human Studies ..................................................21 3.1.2.1. Epidemiologic Studies .....................................22 3.1.2.2. Examination of Clusters or Case Reports/Series ..................31 3.1.3. Other Considerations .............................................31 3.1.3.1. Pharmacokinetics .........................................31 3.1.3.2. Comparisons of Molecular Structure ...........................32 3.2. Dose-Response Evaluation ...............................................32 3.3. Characterization of the Health-Related Database ...............................37 3.4. Determination of the Reference Dose (RfDDT) or Reference Concentration (RfC DT) for Developmental Toxicity ...............................................40 3.5. Summary ............................................................42 iii CONTENTS (continued) 4. Exposure Assessment ........................................................43 5. Risk Characterization ........................................................45 5.1. Overview ............................................................45 5.2. Integration of the Hazard Identification/Dose-Response Evaluation and Exposure Assessment ...........................................................45 5.3. Descriptors of Developmental Toxicity Risk ...................................47 5.3.1. Estimation of the Number of Individuals Exposed to Levels of Concern .........47 5.3.2. Presenting Specific Scenarios ........................................47 5.3.3. Risk Characterization for Highly Exposed Individuals ......................47 5.3.4. Risk Characterization for Highly Sensitive or Susceptible Individuals ...........48 5.3.5. Other Risk Descriptors .............................................48 5.4. Communicating Results ..................................................49 6. Summary and Research Needs .................................................50 7. References ................................................................51 Part B: Response to Public and Science Advisory Board Comments 1. Introduction ...............................................................63 2. Intent of the Guidelines .......................................................64 3. Basic Assumptions ..........................................................64 4. Maternal/Developmental Toxicity ................................................65 5. Functional Developmental Toxicity ...............................................65 iv 6. Weight-of-Evidence Scheme ...................................................66 7. Applicability of the RfDDT Concept and the Benchmark Dose Approach ..................67 LIST OF TABLES Table 1. Endpoints of maternal toxicity ..............................................8 Table 2. Endpoints of developmental toxicity .........................................10 Table 3. Categorization of the health-related database for hazard identification/dose-response evaluation ............................................................38 LIST OF FIGURES Figure 1. Graphical illustration of the benchmark dose approach ...........................35 v GUIDELINES FOR DEVELOPMENTAL TOXICITY RISK ASSESSMENT [FRL-4038-3] AGENCY: U.S. Environmental Protection Agency (EPA). ACTION: Final Guidelines for Developmental Toxicity Risk Assessment. SUMMARY: The U.S. Environmental Protection Agency (EPA) is today issuing final amended guidelines for assessing the risks for developmental toxicity from exposure to environmental agents. As background information for this guidance, this notice describes the scientific basis for concern about exposure to agents that cause developmental toxicity, outlines the general process for assessing potential risk to humans because of environmental contaminants, summarizes the history of these guidelines, and addresses public and Science Advisory Board comments on the 1989 “Proposed Amendments to the Guidelines for the Health Assessment of Suspect Developmental Toxicants” [54 FR 9386-9403]. These guidelines, which have been renamed “Guidelines for Developmental Toxicity Risk Assessment” (hereafter “Guidelines”), outline principles and methods for evaluating data from animal and human studies, exposure data, and other information to characterize risk to human development, growth, survival, and function because of exposure prior to conception, prenatally, or to infants and children. These Guidelines amend and replace EPA’s 1986 “Guidelines for the Health Assessment of Suspect Developmental Toxicants” [51 FR 34028-34040] by adding new guidance on the relationship between maternal and developmental toxicity, characterization of the health-related database for developmental toxicity risk assessment, use of the reference dose or reference concentration for developmental toxicity (RfDDT or RfC DT), and use of the benchmark dose approach. In addition, the Guidelines were reorganized to combine hazard identification and dose-response evaluation since these are usually done together in assessing risk for human health effects other than cancer. EFFECTIVE DATE: The Guidelines will be effective December 5, 1991. FOR FURTHER INFORMATION, CONTACT: Dr. Carole A. Kimmel, Effects Identification and Characterization Group, National Center for Environmental Assessment-Washington Division (8623D), U.S. Environmental Protection Agency, 401 M Street, SW, Washington, DC 20460, TEL: 202-564-3307, FAX: 202-565-0078. vi SUPPLEMENTARY INFORMATION: The Clean Air Act (CAA), the Toxic Substances Control Act (TSCA), the Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA), and other statutes administered by the EPA authorize the Agency to protect public health against adverse effects from environmental pollutants. One type of adverse effect of great concern is developmental toxicity, i.e., adverse effects produced prior to conception, or during pregnancy and childhood. Exposure to agents affecting development can result in any one or more of the following manifestations of developmental toxicity: death, structural abnormality, growth alteration, and/or functional deficit. These manifestations encompass a wide array of adverse developmental endpoints, such as spontaneous abortions, stillbirths, malformations, early postnatal mortality, reduced birth weight, mental retardation, sensory loss, and other adverse functional or physical changes that are manifested postnatally. The Role of Environmental Agents in Developmental Toxicity Several environmental agents are established as causing developmental toxicity in humans (e.g., lead, polychlorinated biphenyls, methylmercury, ionizing radiation), while many others are suspected of causing developmental toxicity in humans on the basis of data from experimental animal studies (e.g., some pesticides, other heavy metals, glycol ethers, alcohols, and phthalates). Data for several of the agents identified as causing human developmental toxicity have been compared to the experimental animal data (Nisbet and Karch, 1983; Kimmel et al., 1984; Hemminki and Vineis, 1985; Kimmel et al., 1990a). In these comparisons, the agents causing human developmental toxicity in almost all cases were found to produce effects in experimental animal studies and, in at least one species tested, types of effects similar to those in humans were generally seen. This information provides a strong basis for the use of animal data in conducting human health risk assessments. On the other hand, a number of agents found to cause developmental toxicity in experimental animal studies have not shown clear evidence of hazard in humans, but the available human data are often too limited to evaluate a cause- and-effect relationship. The comparison of dose-response relationships is hampered
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